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Function of glutamate delta-1 receptor

Award Number: R01MH116003
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Function of glutamate delta-1 receptor - Summary: The delta family of ionotropic glutamate receptors consisting of glutamate delta 1 (GluD1) and glutamate delta 2 (GluD2) are unusual since they do not exhibit typical ligand-gated ionic currents. Instead, they are endowed with synaptogenic property by forming a trans-synaptic GluD-Cerebellin1 (Cbln1)-Neurexin complex and inducing synapse formation. In addition, the GluD receptors have C-terminal interactions which may stabilize postsynaptic density machinery and contribute to synaptic plasticity. Although the function of GluD2 subunit in the formation and plasticity of parallel fiber-Purkinje cell synapse in the cerebellum is well established the role of GluD1 enriched in the forebrain remains largely unknown. This has important implications for our understanding of neurodevelopmental and schizoaffective disorders since GRID1 gene that codes for GluD1 is strongly associated with autism, schizophrenia, bipolar disorder and major depression. In addition, Neurexin1 is also highly associated with mental disorders and both Cbln1 and Neurexin1 splice variant levels change in an activity-dependent manner and are therefore susceptible to pathological insult. Thus, the GluD1-Cbln1-Neurexin complex is a highly vulnerable node for emergence of neurocognitive disorders. GluD1 is enriched in the striatum which receives strong excitatory inputs from the cortex and thalamus. Our preliminary results demonstrate a critical role of GluD1 in excitatory neurotransmission in medium spiny neurons in the striatum. Our goal is to address potential cell-type and synapse-selectivity in this effect upon loss of GluD1 which will support its role as a synaptic organizer. We will pursue the following specific aims; (i) Determine the ultrastructural localization of GluD1 in the striatum and the effect of GluD1 loss on synaptic structure. We will use a range of complementary electron microscopy, immunohistochemistry and biochemistry methods to analyze distribution of GluD1 in the striatum and impact of GluD1 loss on striatal synapses and potential reorganization of synaptic components. (ii) Determine the role of GluD1 in synaptic neurotransmission and plasticity. We will use conventional electrophysiology together with ex vivo optogenetics to stimulate specific synapses to address potential synapse-specific roles of GluD1. (iii) Determine the role of striatal GluD1 in cognitive and behavioral control. We will address the impact of changes in synaptic function upon loss of striatal GluD1 on emotional, cognitive and motor behaviors that are regulated by striatal circuits. These studies will be complemented with DREADD technique to manipulate specific striatal pathways. Together, the proposed studies will systematically address the synaptic organizational principle of GluD1 in the striatum and address its role in synaptic and behavioral phenotypes relevant to neuropsychiatric and neurological disorders.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = -$131 )
2026	2022	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Mental Health Research Grants	000	6	11/24/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$131
														Subtotal = -$131

Issue Date FY: 2024 ( Subtotal = $7,476 )
2024	2022	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Mental Health Research Grants	003	6	5/21/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$2,808
2024	2022	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Mental Health Research Grants	004	6	7/9/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2024	2022	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Mental Health Research Grants	001	5	4/25/2024	NON-COMPETING CONTINUATION	-$155,373
2024	2022	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Mental Health Research Grants	002	5	5/21/2024	NON-COMPETING CONTINUATION	-$2,808
2024	2022	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Mental Health Research Grants	000	6	4/24/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$162,849
														Subtotal = $7,476

Issue Date FY: 2022 ( Subtotal = $376,429 )
2022	2022	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Mental Health Research Grants	000	5	6/15/2022	NON-COMPETING CONTINUATION	$376,429
														Subtotal = $376,429

Issue Date FY: 2021 ( Subtotal = $376,083 )
2021	2021	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Mental Health Research Grants	000	4	5/26/2021	NON-COMPETING CONTINUATION	$376,083
														Subtotal = $376,083

Issue Date FY: 2020 ( Subtotal = $375,736 )
2020	2020	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Mental Health Research Grants	000	3	5/30/2020	NON-COMPETING CONTINUATION	$375,736
														Subtotal = $375,736

Issue Date FY: 2019 ( Subtotal = $375,390 )
2019	2019	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Mental Health Research Grants	000	2	6/10/2019	NON-COMPETING CONTINUATION	$375,390
														Subtotal = $375,390

Issue Date FY: 2018 ( Subtotal = $386,419 )
2018	2018	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Mental Health Research Grants	000	1	8/3/2018	NEW	$386,419
														Subtotal = $386,419

Grand Total All Awards = $1,897,402

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Function of glutamate delta-1 receptor

Award Number: R01MH116003

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/01/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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